Psychostimulant drugs are addictive, and relapse to drug taking, even after prolonged periods of abstinence,[unreadable] is highly probable. The behavioral and neurochemical responses to psychostimulant drugs that change in[unreadable] concert with amount of drug exposure are thought to play an important role in addiction and relapse. A key[unreadable] hypothesis of Scientific Component 6 is that the seemingly diverse central nervous system alterations[unreadable] associated with addiction are coordinated in ways that are difficult to define by studying each in isolation.[unreadable] Two sets of selectively bred mice will be developed by the Animal Core Component 3 and used to help[unreadable] identify the genes and combinations of genes that influence methamphetamine (MA) self-administration and[unreadable] neuroadaptation. In Specific Aim 1, the genetic relationship between sensitization and self-administration will[unreadable] be examined in lines of mice bred for increased and reduced sensitivity to locomotor sensitization (a[unreadable] measure of neuroadaptation) produced by MA, and in separate lines bred for high and low oral MA self-administration;[unreadable] the operant intracranial MA self-administration model from Scientific Component 5 will be[unreadable] used to validate the oral self-administration model. In Specific Aim 2, full genome scans will be performed to[unreadable] identify genetic loci influencing each of the selected traits. In addition, data will be subjected to a search for[unreadable] epistatic (gene-gene) interactions to provide important insights into the genetic interplay that likely influences[unreadable] these complex traits. In Specific Aim 3, gene expression patterns will be examined in the brains of the[unreadable] selected lines using microarray methods on tissue from specific neuroanatomical locations to get a global[unreadable] picture of what gene expression differences may be associated with the differences in drug sensitivity.[unreadable] Neuroanatomic locations will be informed by Component 5 & pilot 8A. Finally, in Specific Aim 4, other traits[unreadable] that may be genetically correlated with the selection traits will be examined in the selected lines. For[unreadable] example, sensitivity to stress-induced reinstatement of MA-induced conditioned place preference will be[unreadable] examined; possible differences in impulsivity will be assessed using the Delay Discounting Procedure;[unreadable] neurochemical correlates will be examined in collaboration with Component 5. The preclinical genetic[unreadable] findings will be translated to our clinical investigators. Common implication of neuroanatomical pathways[unreadable] found across the Scientific Components could lead to the identification of coordinated pathways that[unreadable] influence addiction.